How are genetic causes of iron deficiency treated?

Treatment of Genetic Causes of Iron Deficiency

Genetic causes of iron deficiency require targeted treatment based on the specific molecular defect, with IRIDA (TMPRSS6 mutations) requiring intravenous iron as oral supplementation is ineffective, while other genetic disorders like hypotransferrinemia and DMT1 defects require specialized approaches including transfusions, intravenous iron, and management of paradoxical iron overload. 1, 2

Diagnostic Approach to Genetic Iron Deficiency

The key to managing genetic iron deficiency is recognizing patterns that distinguish these disorders from common nutritional deficiency 1:

• Suspect genetic causes when: anemia is refractory to oral iron supplementation, there is family history of unexplained anemia, or iron studies show paradoxical patterns (elevated ferritin with low transferrin saturation, or very low transferrin saturation despite treatment) 1
• Critical laboratory patterns include: low TSAT with low-normal ferritin (>20 μg/L) suggesting IRIDA, or elevated ferritin with low TSAT suggesting systemic iron loading disorders 1, 2

Treatment by Specific Genetic Defect

IRIDA (Iron-Refractory Iron Deficiency Anemia - TMPRSS6 Mutations)

Intravenous iron is the cornerstone of treatment as oral iron is characteristically ineffective 1, 2:

• Administer intravenous iron formulations such as iron sucrose or iron gluconate, with total cumulative doses calculated based on hemoglobin deficit and iron store depletion 1
• Dosing for ferric carboxymaltose: For patients ≥50 kg, give 750 mg IV in two doses separated by at least 7 days (total 1,500 mg per course); for patients <50 kg, give 15 mg/kg IV in two doses separated by at least 7 days 3
• Monitor serum ferritin closely and maintain levels preferably below 500 μg/L to avoid iron overload toxicity, especially in children and adolescents 1
• Repeat dosing every 3-7 days until total calculated dose is administered, with single doses not exceeding the maximum recommended 1
• Consider combination therapy with erythropoietin (EPO) in select cases, though evidence is limited; this may prevent toxic iron loading in some patients 1

Hypotransferrinemia (TF Gene Defects)

This rare autosomal recessive disorder presents with the paradox of iron-deficient erythropoiesis alongside systemic iron overload 1, 2:

• Intravenous iron supplementation is the primary treatment, as it bypasses the defective transferrin-mediated iron delivery system 1
• Monitor for systemic iron loading in liver and other organs despite treating the anemia, as non-transferrin-bound iron causes tissue deposition 1
• Manage iron overload complications with chelation therapy when tissue iron accumulation becomes clinically significant 1
• Expect partial response: Treatment improves but does not fully normalize hemoglobin levels due to the fundamental defect in iron transport 1

DMT1 Defects (SLC11A2 Mutations)

Defects in the divalent metal transporter cause impaired intestinal and erythroid iron uptake 1:

• Erythrocyte transfusions are required for patients with severe anemia 1
• Oral iron supplementation paradoxically increased hemoglobin and achieved transfusion independence in one reported patient, despite the theoretical absorption defect 1
• EPO therapy resulted in hemoglobin increases but did not prevent liver iron loading based on limited case reports 1
• Monitor for liver iron accumulation with MRI or biopsy, as systemic iron loading occurs despite anemia (likely through alternative heme absorption pathways) 1
• Avoid excessive iron supplementation as it contributes to hepatic iron overload without necessarily correcting the anemia 1

Sideroblastic Anemias (ALAS2, SLC25A38, STEAP3 Defects)

Treatment varies dramatically by genetic subtype 4:

X-linked Sideroblastic Anemia (ALAS2 defects):

• Initiate pharmacologic doses of pyridoxine (vitamin B6) at 50-200 mg/day as first-line therapy 4
• Maintain lifelong supplementation at 10-100 mg daily for pyridoxine-responsive cases 4
• Monitor iron parameters (ferritin, transferrin saturation) regularly to detect iron loading, which is often of greater consequence than the anemia itself 1, 4
• Implement phlebotomy as the preferred method for managing iron overload when tolerated 4
• Use iron chelation therapy when phlebotomy causes unacceptable anemia or is otherwise contraindicated 4

SLC25A38 defects:

• Hematopoietic stem cell transplantation (HSCT) is the only curative option and should be considered early 4
• Provide symptomatic treatment with erythrocyte transfusions and chelation therapy until definitive HSCT can be performed 4

STEAP3 defects:

• Treat with erythrocyte transfusions combined with erythropoietin (EPO) 4
• Monitor and treat systemic iron loading with chelation therapy as needed 4

Monitoring and Follow-Up

Regular surveillance is essential to balance treating anemia while preventing iron overload complications 1, 4:

• Check hemoglobin, ferritin, and transferrin saturation at baseline, 2 weeks, 4 weeks, 3 months, then every 3 months for the first year 2
• Monitor liver enzymes and assess for liver fibrosis or hepatocellular carcinoma in patients with chronic iron loading 4
• Use MRI of the liver to quantify iron accumulation in patients at risk for iron overload 4
• Check serum phosphate levels in patients requiring repeat IV iron courses within 3 months, as hypophosphatemia is a recognized complication 3

Family Screening and Genetic Counseling

Inform patients about inheritance patterns and screen at-risk family members 1, 4:

• For autosomal recessive disorders (IRIDA, hypotransferrinemia, DMT1 defects): Screen siblings and spouse if consanguineous; screen parents only if of reproductive age 1
• For X-linked disorders (ALAS2): Screen brothers who may be affected; screen mother, sisters, and daughters for carriership 4
• Refer to clinical geneticist for complex genotype-phenotype correlations and rare genetic forms 1, 4

Critical Pitfalls to Avoid

• Never assume oral iron failure is due to noncompliance without considering genetic causes, particularly IRIDA where oral iron is characteristically ineffective 1, 2
• Do not overlook iron overload in genetic anemias; unrecognized tissue iron loading can cause severe morbidity and mortality, particularly in sideroblastic anemias where iron overload is often more consequential than the anemia itself 1
• Avoid excessive IV iron dosing without monitoring ferritin, as maintaining levels below 500 μg/L prevents toxicity especially in pediatric patients 1
• Do not use ferritin alone to assess iron status in inflammatory conditions, as it may be falsely elevated despite true iron deficiency 1